Developing a research study that is comprehensive and optimized for success begins with a solid understanding of what has come before. Whether you're building on a long-term preclinical study, or establishing the framework to begin new work, it's critical to review published research in your study area and to consider methods and protocols that have delivered that peer-approved data. Browse our curated list of publications in which preclinical services were performed in partnership with The Jackson Laboratory.
While regulatory agencies increasingly scrutinize and update requirements related to animal use in research, the need for robust in vivo data still remains critical to ensure the safety and efficacy of new therapeutics entering clinical trials. Non-human primates (NHPs) - the species formerly considered the most reliably translational - are falling out of regulatory favor, as well as bearing high costs to utilize, challenges in availability, and are simply a less feasible option for early-stage testing. Conversely, humanized transgenic mouse models are rapidly becoming the gold standard for preclinical pharmacokinetic (PK) studies.
JAX has developed a suite of humanized mouse models that exclusively express human FcRn, forming the foundation of the HuPK™ platform. These models have been successfully used to predict the clinical PK of antibody-based therapeutics, Fc-engineered variants, and albumin-conjugated drugs with accuracy comparable to NHPs.
The work by Haraya et al. explores the use of human FcRn transgenic mice (Tg32) to predict the pharmacokinetics (PK) of Fc-engineered monoclonal antibodies (mAbs) with enhanced FcRn binding mutations. The study demonstrates that Tg32 mice can effectively predict human PK, providing a viable alternative to cynomolgus monkeys and potentially accelerating the preclinical development of Fc-engineered mAbs. The presence of intravenous immunoglobulin (IVIG) in Tg32 mice mimics human FcRn competition, enhancing the accuracy of PK predictions of half-life enhancing antibodies.
Haraya K., Ichikawa T., Murao N., Katada H., Kuramochi T. (2025). Prediction of human pharmacokinetics of Fc-engineered therapeutic monoclonal antibodies using human FcRn transgenic mice. MAbs, 17(1):2484443. PMID: 40133232
Valente and colleagues investigated the pharmacokinetics (PK) of Fc-engineered monoclonal antibodies (mAbs) and multispecific antibodies in cynomolgus monkeys and in humanized FcRn transgenic mouse models. The study aimed to evaluate the potential of using humanized FcRn transgenic mice to predict human PK. They found that FcRn-binding mutations improved the plasma half-lives of the engineered antibodies, and that the Tg32 FcRn mouse model showed a strong correlation with cynomolgus monkeys in predicting human PK. The results suggest that humanized FcRn mice are a viable alternative to replace non-human primate models to differentiate PK of variants in early drug development and guide the design of further pharmacology and safety studies - providing a cost-effective and more alternative for early in vivo drug discovery and development.
Valente D., Mauriac C., Schmidt T., Focken I., Beninga J., Mackness B., Qiu H., Vicat P., Kandira A., Radošević K., Rao S., Darbyshire J., Kabiri M. (2020). Pharmacokinetics of novel Fc engineered monoclonal and multispecific antibodies in cynomolgus monkeys and humanized FcRn transgenic mouse models. MAbs,12(1):1829337. PMID: 33079615
This study focuses on the engineering of antibody Fc regions to enhance their binding to the neonatal Fc receptor (FcRn) and thereby extend their plasma half-life. This study combines rational design and mutations to generate novel antibody variants with improved pharmacokinetic properties and acceptable development profiles.
Mackness B.C., Jaworski J.A., Boudanova E., Park A., Valente D., Mauriac C., Pasquier O., Schmidt T., Kabiri M., Kandira A., Radošević K., Qiu H. (2019). Antibody Fc engineering for enhanced neonatal Fc receptor binding and prolonged circulation half-life. MAbs,11(7):1276-1288. PMID: 31216930
In the absence of reliable preclinical data to predict the PK of antibody therapeutics in humans, Phase 1 clinical trials often rely on dose escalation studies - an approach that increases the risk of suboptimal efficacy, adverse side effects, and clinical failure.
JAX's FcRn humanized “Tg276” mice (strain #004919), which ubiquitously express human FCGRT at high levels in all tissues, and humanized “Tg32” mice (strain #014565), which express human FCGRT in a physiologically relevant pattern, offer robust in vivo platforms for identifying promising lead variants and predicting human antibody PK for allometric scaling. By incorporating FcRn transgenic mice into the preclinical development pipeline and allometric scaling workflows, you can easily identify lead drug candidates and aids in estimating therapeutic window of antibodies, reducing the need for risky and resource-intensive dose escalations in early-phase trials.
Sam and colleagues (2024) explored the development and evaluation of a bispecific CD19-targeted CD28 agonist (CD19-CD28) designed to enhance the efficacy of glofitamab, a CD20-targeted T-cell bispecific antibody (TCB). The study goal was to provide effective CD28 costimulation to glofitamab-activated T cells without super-agonistic properties, thereby improving antitumor responses. Humanized FcRn Tg32 mice were used to guide the dose and schedule of CD19-CD28 for clinical trials, enabling accurate predictions of human pharmacokinetics and supporting the safe and effective use of this novel immunotherapy.
Sam J., Hofer T., Kuettel C., Claus C., Thom J., Herter S., Georges G., Korfi K., Lechmann M., Eigenmann M.J., Marbach D., Jamois C., Lechner K....Umaña P. (2024). CD19-CD28: an affinity-optimized CD28 agonist for combination with glofitamab (CD20-TCB) as off-the-shelf immunotherapy. Blood,143(21):2152-2165. PMID: 38437725
Gjølberg and colleagues investigated how the biophysical properties of IgG1 Fc-based therapeutics influence their interaction with the neonatal Fc receptor (FcRn), cellular handling, and plasma half-life. Humanized FcRn Tg32 mice were instrumental in validating the differences in pharmacokinetic properties and cellular handling between the Fc fragment and full-length IgG1, as well as the impact of Fc fusion partners on these processes.
Gjølberg T.T., Frick R., Mester S., Foss S., Grevys A., Høydahl L.S., Jørstad Ø.K., Schlothauer T., Sandlie I., Moe M.C., & Andersen J.T. (2022). Biophysical differences in IgG1 Fc-based therapeutics relate to their cellular handling, interaction with FcRn and plasma half-life. Communications Biology, 5, 832. PMID: 35982144
With its FcRn-binding capability for extended half-life, albumin is increasingly being used as a carrier for conjugated or genetically fused therapeutic moieties. Due to cross-species differences in FcRn-albumin binding, the utility of traditional mouse models to accurately predict the human PK of these therapeutics has been limited. To address this, JAX's HuPK™ portfolio includes human FcRn transgenic mouse models carrying additional, targeted mutations and transgenes to enable more accurate PK assessment of albumin-based drugs.
The Alb KO (strain #025201) expresses human FcRn and lacks both mouse albumin and FcRn, eliminating high-affinity competition that can confound PK assessments. The Tg32 hALB (strain #037524) builds on this model by also expressing human albumin, enabling evaluation of albumin-based drugs in a more physiologically relevant environment.
Foss and colleagues aimed to design more potent monoclonal human IgG antibodies to improve therapeutic efficacy. They developed an Fc-engineered variant with three amino acid substitutions Q311R/M428E/N434W (REW) and used human FcRn Tg32 transgenic mice to investigate the pharmacokinetic properties and therapeutic potential. The engineered antibody exhibited an extended plasma half-life, enhanced mucosal distribution, and improved complement-mediated killing of cancer cells as well as both gram-positive and gram-negative bacteria.
Foss S., Sakya S.A., Aguinagalde L., Lustig M., Shaughnessy J., Cruz A.R., Scheepmaker L., Mathiesen L., Ruso-Julve F., Anthi A.K., Gjølberg T.T., Mester S., Bern M., Evers M., Bratlie D.B., Michaelsen T.E., Schlothauer T., Sok D., Bhattacharya J., Leusen J., Valerius T., Ram S., Rooijakkers S.H.M., Sandlie I., & Andersen J.T. (2024). Human IgG Fc-engineering for enhanced plasma half-life, mucosal distribution and killing of cancer cells and bacteria. Nature Communications, 15(1), 2007. PMID: 38453922
Bern and colleagues engineered a human albumin variant, QMP (E505Q/T527M/K573P), to enhance binding to the neonatal Fc receptor (FcRn), a key mediator of transcytosis across epithelial barriers and prolongation of the plasma half-life of protein therapeutics. To evaluate the pharmacokinetics, biodistribution, and mucosal uptake efficiency of the albumin variants, the authors employed several FcRn mouse models, including FcRn knock-out (KO), Tg32, and Tg32 albumin KO mice. These models were instrumental in demonstrating that the engineered albumin exhibited improved mucosal delivery and extended plasma half-life. The findings provide valuable insights for the design of more efficient FcRn-targeted drug delivery systems.
Bern M., Nilsen J., Ferrarese M., Sand K.M.K., Gjølberg T.T., Lode H.E.... & Andersen J.T. (2020). An engineered human albumin enhances half-life and transmucosal delivery when fused to protein-based biologics. Science Translational Medicine, 12(565), eabb0580. PMID: 33055243
Blocking the binding between IgG and FcRn has emerged as a promising therapeutic strategy for treating autoimmune and alloimmune conditions. By blocking the IgG binding to FcRn, these therapies aim to accelerate clearance and reduce levels of disease-causing immunoglobulins. To support the development and optimization of such therapeutics, JAX's HuPK™ portfolio offers cutting-edge human FcRn transgenic mouse models. These models incorporate specific mutations and human transgenes designed to closely replicate human PK, providing a more predictive in vivo platform for evaluating FcRn antagonists and human IgG-based drugs.
Seth and colleagues characterized the molecular, cellular, and nonclinical characteristics of nipocalimab, a human IgG1 monoclonal antibody designed to block the neonatal Fc receptor (FcRn). This blockade results in the reduction of circulating IgG levels, including pathogenic IgG antibodies, which have potential therapeutic applications in IgG-driven, autoantibody- and alloantibody-mediated diseases. Humanized FcRn Tg32 mice were instrumental in demonstrating the efficacy of nipocalimab in reducing IgG levels and ameliorating disease symptoms in autoantibody-mediated conditions.
Seth N.P., Xu R., DuPrie M., Choudhury A., Sihapong S., Tyler S., Meador J., Avery W., Cochran E., Daly T., Brown J., Rutitzky L., Markowitz L., Kumar S....Ling L.E. (2025). Nipocalimab, an immunoselective FcRn blocker that lowers IgG and has unique molecular properties. MAbs, 17(1):2461191. PMID: 39936406